Faculty Bibliography

The higher incidence rate of Alzheimer's disease (AD) in elderly women indicates that gender plays a role in AD pathogenesis. Evidence from clinical and pharmacologic studies, neuropathological examinations, and models of hormone replacement therapy suggest that cholinergic basal forebrain (CBF) cortical projection neurons within the nucleus basalis (NB), which mediate memory and attention and degenerate in AD, may be preferentially vulnerable in elderly women compared to men. CBF neurons depend on nerve growth factor (NGF) and their cognate receptors (trkA and p75(NTR)) for their survival and maintenance. We recently demonstrated a shift in the balance of NGF and its receptors toward cell death mechanisms during the progression of AD. To address whether gender affects NGF signaling system expression within the CBF, we used single cell RNA amplification and custom microarray technologies to compare gene expression profiles of single cholinergic NB neurons in tissue specimens from male and female members of the Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. p75(NTR) expression within male cholinergic NB neurons was unchanged across clinical diagnosis, whereas p75(NTR) mRNA levels in female NB neurons exhibited a approximately 40% reduction in AD compared to NCI. Male AD subjects displayed a approximately 45% reduction in trkA mRNA levels within NB neurons compared to NCI and MCI. In contrast, NB neuronal trkA expression in females was reduced approximately 50% in both MCI and AD compared to NCI. Reduced trkA mRNA levels were associated with poorer global cognitive performance and higher Braak scores in the female subjects. In addition, we found a female-selective reduction in GluR2 AMPA glutamate receptor subunit expression in NB neurons in AD. These data suggest that cholinergic NB neurons in females may be at greater risk for degeneration during the progression of AD and support the concept of gender-specific therapeutic interventions during the preclinical stages of the disease.

Background: Although the hippocampus is selectively vulnerable to neurodegeneration during the early stages of Alzheimer's disease (AD), the molecular and cellular mechanisms underlying this dysfunction are poorly understood. Nerve growth factor, itscognate receptors and downstreamevents aswell as endosomal- lysosomal systemimpairmentmayunderlie hippocampal dysfunction during the progression of AD.Methods: To explore the role of thesemolecular factors in hippocampal degeneration during the progression of AD we performed single population gene expression array analysis and quantitative immunoblotting on tissues obtained from subjects who died with an antemortem clinical diagnosis of nocognitive impairment (NCI), mild cognitive impairment (MCI), or AD. Expression profiling observations were validated with real-time qPCR and immunocytochemistry. Results: In the present investigation, we found an increase in hippocampal protein levels of proNGF (p = 0.027) and to a lesser extent phopho-JNK (Ser 473, p = 0.066) in AD compared to NCI andMCI. Hippocampal p75^NTR remained stable across the three clinical groups while TrkA levels were reduced w60% in MCI compared to NCI orAD. No differences were found in sortilin, NRH2, phospho-AKT, phospho- ERK1/2 orAKT, ERK1/2 and JNK in the hippocampus across groups. ProNGF levels were positively correlated with phospho-JNK and to a lesser extent to phospho-AKT, suggesting activation of downstream cell survival and stress activation signals. Increased proNGF and phospho-JNK levels were associated with lower MMSE scores but not Braak neuropathology. Phospho-AKT and phosphor-ERK1/2levels were not associated with MMSE or Braak stage. On the other hand, single cell expression profiling of hippocampal CA1 neurons indicate a significant upregulation of early endosome effectors rab4 (AD>MCI&NCI) and rab5 (AD>MCI>NCI), late endosome constituent rab7 (AD &MCI > NCI), and the trafficking molecule rab24 (AD > MCI & NCI). Down regulation of thesynaptic-related marker r!

The Autism Tissue Program (ATP), a science program of Autism Speaks, provides researchers with access to well-characterized postmortem brain tissues. Researchers access these tissues through a peer-reviewed, project-based approval process, and obtain related clinical information from a secure, online informatics portal. However, few of these samples have DNA banked from other sources (such as a blood sample from the same individual), hindering genotype-phenotype correlation and interpretation of gene expression data derived from the banked brain tissue. Here, we describe an initiative to extract DNA from Brodmann Area 19, and genotype these samples using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Human1M-Duo DNA Analysis BeadChip genome-wide microarray technologies. We additionally verify reported gender, and infer ethnic background from the single nucleotide polymorphism data. We have also used a rigorous, multiple algorithm approach to identify genomic copy number variation (CNV) from these array data. Following an initial proof of principle study using two samples, 52 experimental samples, consisting of 27 subjects with confirmed or suspected autism and related disorders, 5 subjects with cytogenetically visible duplications of 15q, 2 with epilepsy and 18 age-matched normal controls were processed, yielding high-quality genotype data in all cases. The genotype and CNV data are provided via the ATP informatics portal as a resource for the autism research community

The median eminence of the hypothalamus is an important conduit by which neurosecretory hormones from hypothalamic nuclei are delivered to the pars nervosa (neural lobe) of the pituitary en route tothe bloodstream. Dilutional hyponatremia was produced in adult ratsto determine the effect on the morphology of the median eminence of the hypothalamus. Hyponatremia was caused by reducing electrolyte and organic osmolyte reserves to block the excretion of water through delivery of the nephrotoxin mercuric chloride (HgCl2). Histological examination of the brain 1 day after a hyponatremic insult revealed vacuolation within the median eminence of the hypothalamus. No other lesions were found in other parts of the brain after hyponatremia. The hyponatremic lesion consisted of a band of closely packed vacuoles that crossed the floor of the third ventricle. Vacuoles associated with hyponatremia were predominantly in the subependymal, fiber, reticular, and palisade layers of the median eminence. Vacuolation was not observed in the tanycyte layer of the median eminence. This study indicates that the median eminence is a potentially vulnerable site in human hyponatremic conditions that should be evaluated further in relevant animal models